What are the recommended treatment options for metastatic myxofibrosarcoma, including first‑line systemic therapy, surgical or radiotherapy approaches for resectable disease, and second‑line agents?

Treatment of Metastatic Myxofibrosarcoma

For metastatic myxofibrosarcoma, anthracycline-based chemotherapy (doxorubicin) is the standard first-line systemic treatment, with surgical resection reserved for isolated, completely resectable metastases (particularly lung metastases with disease-free interval ≥1 year), and second-line options including trabectedin, pazopanib, gemcitabine/docetaxel, or pembrolizumab in selected cases. 1

First-Line Systemic Therapy

Standard Approach

• Doxorubicin monotherapy is the standard first-line treatment for metastatic myxofibrosarcoma 1
• Single-agent doxorubicin has Level I, A evidence as first-line therapy for advanced soft tissue sarcomas including myxofibrosarcoma 1
• No formal demonstration exists that multiagent chemotherapy improves overall survival compared to doxorubicin alone 1

Combination Chemotherapy Considerations

• Doxorubicin plus ifosfamide may be considered when tumor response would be advantageous (e.g., to facilitate subsequent surgery or improve symptoms) and patient performance status is good 1
• This combination achieves higher response rates and improved progression-free survival, though not overall survival benefit 1
• The combination is particularly appropriate in subtypes sensitive to ifosfamide when rapid cytoreduction is needed 1

Surgical Management of Metastatic Disease

Resectable Lung Metastases

• Metachronous lung metastases (disease-free interval ≥1 year) without extrapulmonary disease should be surgically resected if complete excision is feasible 1
• This represents standard treatment with Level IV, B evidence 1
• Mandatory staging before lung metastasectomy includes abdominal CT and bone scan or FDG-PET to confirm isolated lung disease 1
• Chemotherapy may be added perioperatively, preferably neoadjuvant to assess tumor response, particularly with adverse prognostic factors (short disease-free interval, multiple lesions) 1

Synchronous Lung Metastases

• Standard treatment is chemotherapy first 1
• Surgery of completely resectable residual lung metastases may be offered if tumor response is achieved 1

Extrapulmonary Metastases

• Chemotherapy is standard treatment for extrapulmonary metastatic disease 1
• Surgery of responding metastases may be offered in highly selected cases after multidisciplinary evaluation, considering site and individual disease natural history 1

Second-Line and Beyond Systemic Therapy

Established Options

• Trabectedin is a standard second-line option with Level I, B evidence 1

  • Approved for advanced previously treated soft tissue sarcomas in the EU 1
  • Particularly effective in leiomyosarcoma and liposarcoma 1

• Pazopanib is an option for non-adipogenic sarcomas (which includes myxofibrosarcoma) with Level I, B evidence 1

• Gemcitabine/docetaxel or gemcitabine/dacarbazine combinations are options in doxorubicin-pretreated patients 1

  • Level II, B evidence for these combinations 1

• Ifosfamide (if not previously used) is a standard second-line option 1

  • High-dose ifosfamide (around 14 g/m²) may be considered even for patients who received standard-dose ifosfamide previously 1

Emerging Targeted Options

• Pembrolizumab is included as a subsequent-line option specifically for myxofibrosarcoma 1

  • Appropriate for tumor mutational burden-high (≥10 mutations/megabases) disease that has progressed after prior treatment 1
  • Also considered for myxofibrosarcoma based on histology-specific activity 1

• Regorafenib is an option in doxorubicin-pretreated advanced, non-adipogenic sarcomas with Level II, C evidence 1

Radiation Therapy in Metastatic Disease

• Radiation therapy should be used as a palliative resource for symptomatic metastases (e.g., bone lesions at risk of fracture, painful sites) 1
• Stereotactic radiotherapy is an option for oligometastatic disease management 1

Critical Treatment Pitfalls to Avoid

Chemotherapy Resistance Considerations

• Myxofibrosarcoma may be a chemotherapy-resistant entity requiring closer monitoring during neoadjuvant treatment 2
• Chemotherapy did not significantly impact distant metastasis-free survival in localized disease, suggesting inherent resistance 2
• This resistance pattern should temper expectations for systemic therapy in metastatic disease 2, 3

Performance Status Considerations

• Do not offer systemic chemotherapy to patients with performance status 3-4; best supportive care only is appropriate 1
• Treatment recommendations must be guided by performance status, disease extent, rate of progression, and potential sensitivity to treatment 1

Surgical Selection Criteria

• Do not attempt metastasectomy unless complete excision of all lesions is feasible 1
• Incomplete resection does not provide benefit and should be avoided 1

Prognosis and Monitoring

• Median survival with systemic treatments for advanced soft tissue sarcomas is 12-18 months 1
• Tumor size ≥cT3 and grade 3 disease are negative predictive factors for distant metastasis 2
• Approximately 17% of patients with localized myxofibrosarcoma develop distant metastases 2
• The 5-year metastasis-free survival for localized disease is approximately 80-83% 4, 2